tbuckley/cabot-search huggingface dataset:
Abstract 3171: Detecting ploidy specific vulnerability to resource restriction: An integrated <i>in vitro</i> and <i>in silico</i> approach
Authors: Richard J. Beck, Didem Ilter, Ana P. Gomes, Noemi Andor
Journal: Cancer Research (2023)

Abstract Changes in the number of copies of the genome, i.e. changes in ploidy are widespread among cancer cells. Increased ploidy is thought to benefit cancer cells by conferring robustness against deleterious consequences of genomic instability. However, whether there are any potential costs associated with increased ploidy has not been sufficiently investigated. One hypothesis holds that high ploidy cells may exhibit increased sensitivity to limitations in resources, due to the extra energy required for the replication of a larger genome. To address this hypothesis, we developed an integrated in vitro and in silico system to investigate the response to glucose restriction in diploid and tetraploid cells. Near diploid (2N) SUM159 breast cancer cells were fused to generate an isogenic tetraploid (4N) cell line. 2N or 4N cells were plated with varying initial concentrations of glucose. Cells grew for five days and media was not refreshed, so cells depleted the glucose in the media until they eventually died. Throughout the experiments, glucose concentration was measured at 24 hour intervals, and images were taken at 8 hour intervals allowing quantification of the number of alive or dead cells over time. These in vitro data were then used as inputs to the in silico portion of our system, which consists of an Ordinary Differential Equation (ODE) model of cancer cell growth. ODE model parameters were estimated using the measured outputs from the in vitro experiments. Parameters estimated from the ODE model gave insight into differences between the 2N and 4N cell lines. We found that 4N cells outcompeted 2N cells at high glucose concentrations, due to their ability to divide more rapidly when glucose was abundant. However, 2N cells were able to outcompete 4N cells at lower glucose concentrations. The advantage of 2N cells at low glucose was not due to an increased proliferative capacity. Instead, 2N cells were more resistant to cell death when glucose was limited. Our next steps will be to expand our system to assess ploidy specific sensitivity to other resources, such as phosphate or oxygen. The ODE model we have developed allows us to identify resource conditions that will select for tumor cells based on ploidy. In future this knowledge can be used to suggest therapeutics that can modulate resource availability within tumors, in order to steer tumor evolution towards less aggressive phenotypes. Citation Format: Richard J. Beck, Didem Ilter, Ana P. Gomes, Noemi Andor. Detecting ploidy specific vulnerability to resource restriction: An integrated in vitro and in silico approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3171.
Abstract 5016: IL-6 influences PIM1 expression in renal cell carcinoma
Authors: Kimberly S. Meza, Sheldon L. Holder
Journal: Cancer Research (2023)

Abstract Renal cell carcinoma (RCC) is the most common kidney neoplasm, accounting for over 430,000 new cases worldwide and 179,000 deaths annually. The overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in patients with RCC. PIM1 is a constitutively active effector serine/threonine kinase with roles in tumor progression including cell proliferation, apoptosis, invasion, and migration. Yet, the mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine involved in the activation of the JAK/STAT signaling cascade. High serum IL-6 levels are implicated in the poor prognosis of RCC patients and are hypothesized to contribute to RCC invasion and metastasis. PIM1 is shown to be transcriptionally regulated downstream of JAK/STAT signaling and an IL-6/STAT3/PIM1 axis exists in pancreatic cancer. We thus hypothesize that this pathway also regulates expression of PIM1 in RCC. Here, we explore the levels of PIM1 in RCC and identify potential signaling pathways influencing PIM1 expression. Our results show five RCC cell lines, 769-P, 786-O, ACHN, CAKI-1, and RCC-4 cells overexpress PIM1 relative to normal renal proximal tubule epithelial cells. In RCC cell lines, IL-6 secretion correlates with PIM1 protein levels. Treatment with ruxolitinib, a JAK1/2 inhibitor, leads to a dose and concentration dependent decrease in PIM1 levels. We then tested whether incubation with an IL-6 neutralizing antibody is sufficient to regulate PIM1 protein levels. Indeed, use of an IL-6 antibody resulted in decreased pJAK2 protein and PIM1 protein. Our initial studies suggest that differential expression of PIM1 among RCC cell lines may be linked to autocrine IL-6 signaling. Interestingly, 769-P cells demonstrate increased PIM1 levels but do not secrete IL-6 and neither ruxolitinib treatment nor incubation with an IL-6 neutralizing antibody appear to affect PIM1 levels. Therefore, an IL-6/JAK-independent pathway resulting in increased PIM1 protein levels likely exists in 769-P cells. Further investigation is required to elucidate the contexts of PIM1 regulatory pathways in order to develop novel targeted anti-cancer strategies in RCC. Citation Format: Kimberly S. Meza, Sheldon L. Holder. IL-6 influences PIM1 expression in renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5016.
Abstract 5975: Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells
Authors: Chung-Jen Yu, Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng, Jiun-I Lai
Journal: Cancer Research (2023)

Abstract Hormone positive (HR+) breast cancer is the most common subtype in this population. The current standard of care in advanced HR+ breast cancer includes endocrine therapy (tamoxifen, aromatase inhibitors, etc) and CDK4/6 inhibitors. CDK4/6 inhibitors significantly prolong survival and is now the general accepted choice of drug in first line. Despite the enormous clinical benefit, there remains a substantial portion of patients who ultimately develop resistance against CDK4/6 inhibitors. Many mechanisms have been proposed for CDK4/6 inhibitor resistant, including upregulation of CDK4, CDK6, Cyclin E, and others. Recently studies have linked the hippo pathway to CDK6 upregulation and resulting in CDK4/6 inhibitor resistance. We have set up a kinase library screen for kinase inhibitors that downregulate CDK6 amplification and further assess for reversal of resistance. We discovered staurosporine and the PI3K inhibitor PIK-75 as small molecules that potently downregulate CDK6 expression in breast cancer cells. We further confirmed that these compounds reverse the resistance towards CDK4/6 inhibitors in CDK6 amplification cells. By kinase profiling combined with a small hairpin RNA (shRNA) screen, we discovered the mechanisms that resulted in CDK6 downregulation and modulation of the hippo pathway to reverse the CDK4/6 inhibitor resistance. Our discovery has implications for therapeutic development in this group of patients posing a huge unmet need. Citation Format: Chung-Jen Yu, Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng, Jiun-I Lai. Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5975.
Abstract 3280: Vrd induction therapy drives memory like NK cell development in newly diagnosed multiple myeloma patients
Authors: Tao Peng, Emma Kuan, Anthony Cicalo, Qiuyu Gong, Troy Torgerson, Xiaojun Li
Journal: Cancer Research (2023)

Abstract VRd induction therapy is a common approach to treat newly diagnosed multiple myeloma (MM) patients. Although in vitro studies of bortezomib (Velcade, V), lenalidomide (Revlimid, R), and dexamethasone (d) reveal mechanisms of these individual drugs, VRd therapy induced immune cell phenotype changes in vivo are unknown. We have utilized multimodal single cell methods to elucidate novel mechanisms of induction therapy response in human immune cells over time as a longitudinal study: pre-treatment (pretrt), after 2-cycles of VRd therapy (post-induction; pi) and after the end of 4-6 additional cycles of VRd therapy (end induction; ei). Protein measurements in plasma demonstrate significantly increased levels of IL-15 and IL-18 only at pi compared to pretrt but IL-2 and IFN-γ are progressively reduced from pretrt to ei. Both flow cytometry and single cell RNA -seq reveal that the proportion of NK cells (NK) significantly increased in PBMC only at pi compared to pretrt. NK subsets with strong dexamethasone effect emerge at pi; In contrast, memory like NK subsets (CD56dimCD16+NKG2A+CD94+) become the major NK in PBMC and bone marrow (BM) at ei. In addition, single cell ATAC-seq suggests that RUNX-family transcription factors may mediate lenalidomide to up-regulate NK cytotoxic gene expression during VRd therapy. In summary, comprehensive immune profiling of newly diagnosed MM patients suggests that transient increase of IL-15 and IL-18 may mediate the generation of memory like NK cells, which may play important roles in controlling MM growth and/or reducing risk of infection during VRd induction therapy. Citation Format: Tao Peng, Emma Kuan, Anthony Cicalo, Qiuyu Gong, Troy Torgerson, Xiaojun Li. Vrd induction therapy drives memory like NK cell development in newly diagnosed multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3280.
Abstract 4849: PPARγ and FoxO1 expression and activity in aqueous cinnamon extract treated cells
Authors: Sean Mild, Cole Swartz, Amy Aulthouse, Amy Stockert
Journal: Cancer Research (2023)

Abstract Peroxisome-proliferator activated receptor (PPARγ) has been proven to have inhibitory effects on tumor angiogenesis. Research has demonstrated that natural PPARγ ligands are anti-tumorigenic due to growth inhibition and anti-proliferative effects. Cinnamon is one potential PPARγ ligand tested to explore its effects on PPARγ and FoxO1 expression and activity. Literature also suggests that breast cancer proliferation is increased with obesity and co-cultures of adipocytes with MCF-7 cells have suggested an increase in lipase activity. We therefore sought to explore the effects of cinnamon on these transcription factors and lipase activity in 3T3-L1 cells to determine if cinnamon is a plausible co-therapeutic for breast cancer patients. 3T3-L1 cells were cinnamon treated for 48-96 hours post differentiation. Nuclear protein was extracted for ELISA quantification of PPARγ and FoxO1 binding potential. Cytosolic and nuclear protein extracts were analyzed via Western blot of FoxO1 and PPARγ. Copy DNA was produced from the total RNA and expression levels of PPARγ and FoxO1 were examined by TaqMan real-time PCR assays. A lipase activity assay was performed on freshly extracted protein from cultured cells. Western blot data demonstrates an increase in FoxO1 protein with cinnamon treatment at 96 hours post differentiation. PPARγ data shows no significant changes in protein quantity, however ELISA data suggests increases in binding potential PPARγ as well as FoxO1 transcription factors with cinnamon treatment. Preliminary expression analysis suggests changes in both PPARγ and FoxO1. Lipase activity data suggests a significant increase in cinnamon treated adipocytes. Data from the study suggests that cinnamon activates PPARγ and that it may play a role in decreasing tumorigenic activity. However, with particular concern in breast cancer cells, the activation of PPARγ in adipocytes appears to increase the lipase activity, thus producing more free fatty acids and potentially enhancing energy dependent proliferation. Citation Format: Sean Mild, Cole Swartz, Amy Aulthouse, Amy Stockert. PPARγ and FoxO1 expression and activity in aqueous cinnamon extract treated cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4849.
Abstract 4384: Does progressive disease justify pembrolizumab discontinuation: a simulation analysis
Authors: Kannan Thiagarajan, Madhav Channavazzala, Brian Gregory Topp
Journal: Cancer Research (2023)

Abstract Background: With checkpoint inhibition becoming first line therapy in several cancer indications, there is a growing number of patients that are refractory to PD1 therapy. It is unclear if these patients should remain on PD1 inhibitors while new therapies are added on top or if PD1 should be discontinued when new therapies are initiated. Here we simulate a randomized controlled study comparing pembrolizumab + a checkpoint inhibitor (P+C) to a checkpoint inhibitor (C) in virtual patients that are refractory to PD1 therapy. Methods: An IO QSP model was developed that includes intra-patient heterogeneity in tumor dynamics (target, non-target, and new metastatic lesions). The model was calibrated to individual lesion data from a large multicentre, open-label phase III study (Keynote-001) in patients with metastatic melanoma. A two year phase III study comparing P+C to C was simulated with 310 virtual patients in each group. Virtual patients were removed from the trial at the time of RECISTv1.1 progression or dropout due to AE or loss to follow-up. Results: Virtual patients in the P+C arm displayed deeper (-11.5% vs 24.5%) and longer response (186.4 days vs 96.5 days) than virtual patients in the CPI arm. The percent of virtual patients displaying low prevalence progression (&amp;lt; 50% of the target lesions with PD) was 86% vs 52% for P+C vs. C. Median progression free survival was also longer in the P+C arm (3.8 vs 2.1 months). Difference in progression free survival were driven mainly by virtual patients that displayed oligoprogression during the pembrolizumab monotherapy run-in period. Conclusions: Simulations presented here show that virtual patients that continued pembrolizumab treatment beyond RECISTv1.1 progression (as part of a combination) did better than virtual patients that discontinue pembrolizumab (and switch to a new therapy). Citation Format: Kannan Thiagarajan, Madhav Channavazzala, Brian Gregory Topp. Does progressive disease justify pembrolizumab discontinuation: a simulation analysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4384.
Abstract 3491: Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates
Authors: Jason Z. Zhang, William H. Nguyen, John C. Rose, Shao-En Ong, Dustin J. Maly, David Baker
Journal: Cancer Research (2023)

Abstract While Ras is known to dynamically shuttle around the cell, the activity, mechanism of activation, and function of non-plasma membrane-localized Ras is unclear due to lack of suitable tools. To address these questions, we used the Latching Orthogonal Cage-Key pRotein (LOCKR) switch platform to generate first-in-class intracellular sensors for endogenous Ras activity (Ras-LOCKR-S) and signaling-dependent proximity labelers (Ras-LOCKR-PL). We find that: 1) Receptor activation leads to endogenous Ras signaling at endomembranes, which is enhanced by golgi-localized guanine exchange factors. 2) Recruitment of SAM68 and MARCKS to oncogenic condensates fuels local Ras signaling and cell growth. 3) Major Vault Protein drives RasG12C inhibitor resistance by enhancing signaling at the golgi and altering mitochondrial metabolism. Together, these results highlight the importance of non-plasma membrane Ras signaling (endomembranes and condensates), and our new sensors should accelerate the discovery of new therapeutic targets. Citation Format: Jason Z. Zhang, William H. Nguyen, John C. Rose, Shao-En Ong, Dustin J. Maly, David Baker. Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3491.
Abstract 596: Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments
Authors: Jiaqiang Cai, Shuai Song, Qing Zong, Qigang Liu, Jian Xu
Journal: Cancer Research (2023)

Abstract Antibody-drug conjugates (ADC) are one of the fastest growing anticancer drugs, which bring cytotoxic drugs into tumors while avoiding high systemic toxicities. To date, all commercial ADCs use intracellular lysosomal cleavage mechanisms for payload release to kill tumor cells which is often limited by the low tumor antigen expression. To this end, a novel systemically stable and extracellular tumor microenvironment activable linker-payload technology platform has been developed. Preclinical assessments demonstrated that the highly hydrophilic linker-payload, which showed limited impact on the hydrophilicity of antibody, prolonged the retention time in vivo and eventually enhanced the in vivo potency of ADC. The linker-payload is stable with less than 2% payload drop-off after 28-day incubation in plasma under physiological conditions in vitro. The high stability was also illustrated by GLP cynomolgus monkey studies and preliminary clinical trial data, with the overlap of ADC and TAb PK profile. Furthermore, a battery in vitro and in vivo cell line-derived xenograft (CDX) mouse model studies showed the linker-payload is stable in normal tissues but efficiently releases the payload in tumor tissues. The ADCs using TMALIN platform elucidated significant anti-tumor activity advantages when compared with those marketed ADCs targeting the same antigen, besides showing an acceptable safety profile in pivotal NHP studies without lung/liver/kidney toxicities. In summary, the TMALIN platform addresses the unmet need of ADCs by releasing the payload extracellularly in tumors and tumor microenvironments on top of the known intracellular lysosomal cleavage mechanisms. Continued clinical validation work is underway for several pipeline candidates as well as investigation into other target areas. Citation Format: Jiaqiang Cai, Shuai Song, Qing Zong, Qigang Liu, Jian Xu. Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 596.
Abstract 5085: Blockade of tumor derived CSF1 promotes an immune-permissive tumor microenvironment
Authors: Maria Del Mar Maldonado, Duane H. Hamilton, Jeffrey Schlom
Journal: Cancer Research (2023)

Abstract The macrophage colony stimulating factor 1 (CSF1) is a chemokine essential for the survival, proliferation, and differentiation of especially mononuclear phagocytes, such as macrophages and monocytes. However, within the tumor microenvironment (TME), CSF1 regulates the production, survival, and recruitment of tumor associated macrophages (TAMs), further promoting a protumorigenic and immunosuppressive M2-like phenotype. Overexpression of CSF1 in breast, prostate, and ovarian cancers has been shown to promote tumorgenicity, invasiveness, and accelerate tumor metastasis. In this study, we demonstrate for the first time, that treating established murine MC38 colon and 4T1 breast carcinoma tumors with a CSF1R blocking antibody promotes the expansion of neoepitope-specific T cells. To assess the role of tumor derived CSF1 in these model systems, we generated and characterized CSF1 CRISPR-Cas9 knockouts. In both models, elimination of tumor-derived CSF1 results in a decreased tumor growth in both syngeneic and immune-compromised mice as compared to the parental cell lines. Inhibition of CSF1/CSF1R signaling axis generated enhanced immunity against 4T1 and MC38 tumor neoepitopes, potentially promoting an immune permissive TME in tumor bearing mice. Combination of a neoepitope targeting cancer vaccine with anti-PDL1 in the MC38 CSF1-/- tumor model significantly decreased tumor growth in vivo. Furthermore, combining CSF1R blockade with adeno-TWIST1 vaccine decreased tumor volume, lung metastasis, and synergistically increased in CD8 T cell infiltration in 4T1 mammary tumors. Analysis of the tumor microenvironment demonstrated increased infiltration in CD8 T cells accompanied by a reduction in tumor associated macrophages following CSF1R inhibition in both tumor models. Our findings confirm the therapeutic potential of combining CSF1 targeting agents with vaccine agents to further modulate anti-tumor immune responses in the tumor microenvironment. Citation Format: Maria Del Mar Maldonado, Duane H. Hamilton, Jeffrey Schlom. Blockade of tumor derived CSF1 promotes an immune-permissive tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5085.
Abstract 3961: Identification of lncRNAs as potential novel therapeutic targets in triple negative breast cancer
Authors: Megan O'Malley, Zohaib Rana, Debina Sarkar, Jolyn Chia, Sarah Diermeier
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) lacks targeted therapies. Recently, our laboratory and other groups described long non-coding RNAs (lncRNAs) as new drivers of TNBC progression, which represent an exciting new avenue for targeted treatments. LncRNAs are the most versatile and diverse class of non-coding RNAs with roles in the progression of TNBC development, including cell proliferation, differentiation, apoptosis, metastasis and drug resistance. LncRNAs have greater tissue-specific expression compared to proteins and can be targeted using nucleotide sequence-specific RNA therapeutics, leading to reduced systemic toxicities when used as a cancer target. Using a combined approach of computational analysis of patient data and CRISPR functional screening, we identified hundreds of lncRNAs as novel drivers of TNBC. We prioritized one lncRNA target (lncTNBC3) with high translational potential. LncTNBC3 knockdown lead to reduced TNBC cell proliferation in two different loss-of-function models. To gain initial insights into the mechanism via which lncTNBC3 functions, RNA sequencing was carried out on knockdown cells, revealing that lncTNBC3 impacts cell cycle and DNA repair pathways. Cell cycle analysis confirmed an increase in G2/M cell cycle arrest upon lncTNBC3 knockdown. In conclusion, we have identified a promising novel lncRNA target with a role in TNBC growth. Citation Format: Megan O'Malley, Zohaib Rana, Debina Sarkar, Jolyn Chia, Sarah Diermeier. Identification of lncRNAs as potential novel therapeutic targets in triple negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3961.